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Abstract Purpose Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA0,TYR3-octreotate ([177Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in female Lewis rats. Methods Animals received 200 MBq of [177Lu]Lu-DOTA-TATE once and/or 5 mg/kg body weight everolimus or placebo weekly for 16 weeks and were divided into four groups (group 1, placebo; group 2, everolimus; group 3, placebo + [177Lu]Lu-DOTA-TATE; group 4, everolimus + [177Lu]Lu-DOTA-TATE). Blood levels of creatinine and blood urea nitrogen (BUN) were assessed weekly to monitor nephrotoxicity, and a full blood count was performed at the time of euthanasia to monitor myelotoxicity. Additionally, renal function was analysed by sequential [99mTc]Tc-mercaptoacetyltriglycine ([99mTc]Tc-MAG3) scintigraphies. Histopathological examination was performed in all the kidneys using a standardized renal damage score (RDS). Results Rats receiving everolimus showed a significantly lower increase in creatinine levels than those receiving placebo. Everolimus therapy reduced white blood count significantly, which was not observed for [177Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [99mTc]Tc-MAG3 showed a compromised initial tracer uptake after PRRT and slower but still preserved excretion after everolimus. Histology showed no significant RDS differences between groups. Conclusion Renal scintigraphy is a highly sensitive tool for the detection of renal function impairment after a combination of everolimus and PRRT. Additional treatment with everolimus does not increase renal and haematological toxicity of PRRT with [177Lu]Lu-DOTA-TATE.

Therapy options for advanced pancreatic neuroendocrine tumors (pNETs) include the mTOR inhibitor everolimus and peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE, however further optimization in the therapeutic landscape is required as response rates are still low. In this study, we investigated the synergistic and potentially enhanced efficacy of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in a mouse model. Baseline [68Ga]Ga-DOTA-TATE PET scans were obtained five days after athymic CD1 mice were inoculated with AR42J tumor cells, before separating the animals into four groups. Group 1 received a placebo, group 2 everolimus, group 3 a placebo and PRRT, and group 4 everolimus and PRRT. The treatment response was monitored by manually measuring the tumor volumes (manual tumor volume, MTV) and conducting sequential [68Ga]Ga-DOTA-TATE PET scans at one, two, and four weeks after treatment induction. The biological tumor volume (BTV) was derived from PET scans using threshold-based volume of interest (VOI) measurements. Tracer uptake was measured semi-quantitatively as a tumor to background ratio (TBR). Mice were euthanized due to excessive tumor growth according to the ethics protocol; blood samples were drawn for the preparation of full blood counts and kidneys were obtained for histological analysis. For the histological assessment, a standardized score (renal damage score, RDS) was used. Full blood counts showed significantly increased numbers of neutrophils and lymphocytes in the groups receiving PRRT. All other parameters did not differ relevantly. In the histological analysis, groups receiving PRRT had a significantly higher RDS, whereas everolimus only tended to cause an increase in the RDS. Mice in groups 1 and 2 had to be euthanized due to excessive tumor growth two weeks after the start of the therapy, whereas follow-up in groups 3 and 4 comprised four weeks. PRRT significantly inhibited tumor growth; the administration of everolimus did not induce an additional effect. A good correlation existed between MTV and BTV. PRRT significantly reduced the TBR. [68Ga]Ga-DOTA-TATE PET is suitable for monitoring tumor growth in the applied model. The high efficacy of [177Lu]Lu-DOTA-TATE is not enhanced by the combination with everolimus.